Gonadotropin-Releasing Hormone (GnRH), often referred to as Luteinizing Hormone Releasing Hormone (LHRH), is a ten amino acid peptide, produced and secreted by the hypothalamus. This peptide is conserved in all mammals and functions in similar fashion in both males and females. The major pharmacologic role of GnRH is to control the pituitary-gondanal axis. GnRH binds to specific receptors on pituitary cells and causes the release of gonadotropins. Subsequently, the gonadotropins exert their pharmacologic activity on the gonads controlling gametogensis and regulating the production of the sex steroids (estrogens, testosterones, and progestins).
Under normal physiological conditions, the hypothalamus produces GnRH in rhythmic pulses. However, if GnRH is present at a constant high level for an extended period of time, the cells of the pituitary become desensitized and cease producing gonadotrophins. Consequently, the cessation of gonadotrophin release causes the cessation of gametogenis and the production of the sex steroids. Thus, the constant presence of GnRH effects not only the reproductive potential, but other any other biological activities linked to the action of the sex steroids. In effect, high and constant levels of GnRH produce effects similar to those seen in female menopause or male castration.
The physiologic effects of menopause in women or castration in men are quite similar, e.g., hot flashes, weight gain, loss of libido, cardiovascular degeneration, osteoporosis, etc. Cardiovascular degeneration and osteoporosis are the two most potentially serious conditions induced by the continuous presence of GnRH. (For further information, see: "Goodman and Gilman's The Pharmacological Basis Of Therapeutics", Eds. Gilman, A. G., Rall, T. W., Nies, A. S., and Taylor, P., 8th Ed., Pergamon Press, NYC, Chap. 56, pp. 1352-1354 (1990)).
There are a variety of pathological conditions for which the continuous administration of GnRH or GnRH agonists have been of benefit. As mentioned supra, GnRH administration causes the cessation of sex steroid production which can be beneficial. For example, in women, the reduction of estrogen levels is very beneficial in the treatment of endometriosis, uterine fibroids, dysfunctional uterine bleeding, and the like; in men, the reduction of testosterone levels is very beneficial in the treatment of prostatic carcinoma, benign prostatic hypertrophy, and the like.
Despite the beneficial effects of continous GnRH, chronic administration can not be safely pursued due the detrimental side-effects, especially osteoporosis and hyperlipidemia (e.g., see: Synarel.TM. (Nafarelin Acetate) in "Physician's Desk Reference", Ed. 47, Medical Economics Co. Inc., Montvale N.J., pp. 2407-2408 (1993)). In general, continous GnRH or GnRH agonists are not used for periods greater than six months. Additionally, there are some potential uses for GnRH, such as birth control (male or female), which are not even able to be studied for extended periods of time due of the side-effect profile.
Although, all the detrimental side-effects of continous GnRH can be reversed by addition of estrogen or testosterone, their addition obviates the beneficial effects attempting to be achieved.
Clearly, it would of great utility to eliminate the detrimental side-effects associated with the continuous and chronic use of GnRH or GnRH agonists with a safe and non-countraproductive agent.